Lack of a suitable small animal model to study HIV pathogenesis and protective immunity prompted the investigation of the cotton rat as a potential permissive host for virus infection. Preliminary studies demonstrated that HIV can infect two species of cotton rats, namely Sigmodon hispidus and S. fulviventer. While no overt disease was evident, the infection could be serially transmitted by whole blood. The main objective of this proposal is to improve the cotton rat model by developing a transgenic strain expressing human CD4, CXCR-4 and CCR-5 receptors and thus increase its susceptibility to productive HIV infection and disease. The specific aims are to: (1) transform four primary cell lines (lung, kidney, T-cell and macrophage) each from S. hispidus and S. fulviventer using the E1 DNA of adenovirus, (2) transfect these cell lines with combinations of the genes coding for human CD4, CXCR-4 and CCR-5; and (3) compare the replication kinetics of several strains of HIV-1 in transfected versus non-transfected cells to determine if there is justification for developing a transgenic cotton rat as a model for HIV infection.